Preliminary Studies on the Absorption, Distribution, Metabolism, and Excretion of THIP in Animal and Man using 14C‐labelled Compound

Abstract

Distribution of radioactivity in rats, serum levels in human volunteers and rats and elimination of radioactivity in volunteers, rats and mice following oral administration of 14C-labeled THIP [3-hydroxy-4,5,6,7-tetrahydrioisoxazolo[5,4C]pyridinium bromide] were investigated. Peak values of radioactivity in the organs and in serum were seen 0.5 h after administration, indicating a rapid absorption. Highest concentrations of radioactivity were in the kidneys, but radioactivity was seen in all investigated tissues including the brain. The ratiodactrivity was mainly excreted with urine (84-93%). TLC of urine from volunteers, rats and mice showed that most of the excreted radioactivity corresponds to unchanged THIP. Three metabolites were found in urine from rats each in amounts of 2-7% of the total dose given. Two of these metabolites were also found in urine from the volunteers in amounts of 30-35% and < 2%, respectively, and in urine from mice in amounts of 21 and 6% of the total dose, respectively. No radioactivity corresponding to unchanged THIP was found in feces, indicating complete absorption of THIP following oral administration. One of the metabolites, the main one in man and mouse, seemed to be a glucuronic acid conjugate of THIP, but the chemical structure of the metabolites has not yet been established. [Among a number of muscimol analogs, synthetized THIP has been found to be a potent and specific GABA agonist.].